To compare the prevalence of parental diabetes between children with and without type 1 diabetes (T1D), and to compare clinical characteristics at diagnosis of T1D in children with, versus without, a family history of diabetes.
Parental diabetes among children with T1D was compared with a general population cohort. Clinical characteristics were compared by family history of diabetes in parents and grandparents of 3,603 children with T1D using relative risk (RR) and ANOVA.
Children with T1D more often had parents with type 2 diabetes (T2D) (RR 1.88; P < 0.001) than did children without diabetes. Children with T1D and a family history of T2D were more likely to be overweight or obese (P = 0.002).
A family history of T2D and being overweight may contribute to increased risk of T1D.
Introduction
Type 1 diabetes (T1D) in children and adolescents constitutes a heterogenous group with varying clinical phenotypes, HLA profiles, and patterns of autoantibodies (1–3). The incidence of T1D, type 2 diabetes (T2D), and obesity is on the rise in many countries (4,5). We previously demonstrated an association between being overweight or obese and having a low-risk HLA genotype in children with T1D and a decreasing proportion of the high-risk HLA-DQ2/DQ8 genotype (6). It is unclear whether a family history of T2D, regardless of obesity status, is more common in children with T1D. We hypothesized that parental family history of T2D is more common in children with T1D than in the general population and that a first- or second-generation family history of diabetes is associated with the clinical phenotype at diagnosis of T1D.
Research Design and Methods
In Sweden, a child with suspected T1D is referred to in-patient care, receives treatment by a pediatric diabetes team, and is clinically classified at onset according to American Diabetes Association criteria (7), with re-evaluation of the diagnosis at follow-up. Patients are followed longitudinally with clinical data in the Swedish National Diabetes Register (8).
The Better Diabetes Diagnosis (BDD) study is population-based and includes >95% of all children aged 0–18 years at diagnosis of diabetes in Sweden (9). Our cohort from the BDD study included children born from 1987 to 2009 and diagnosed with diabetes between 2005 and 2010.
Between May 2005 and December 2010, 4,088 patients were included in the BDD study. Children with types of diabetes other than T1D or nonclassified diabetes were excluded, as were those missing antibody results, not wanting to participate, and dropouts (n = 441). Patients with more than two missing variables were excluded (n = 44), leaving 3,603 children in total.
Blood samples and clinical characteristics were collected at diagnosis. Data on first- and second-generation family history of diabetes were collected by a diabetes nurse or physician, recorded in the BDD register, and categorized into four groups: family history of T1D only, T2D only, both type 1 and T2D, and no family history of diabetes.
Weight and height data were collected from the National Diabetes Register at a mean duration of 3 months after diagnosis, and BMI was calculated and categorized as normal weight, overweight (age- and sex-adjusted BMI [ISO-BMI] >25 kg/m2) or obese (ISO-BMI >30 kg/m2) (10). BMI was not calculated for children younger than 2 years (n = 106). Diabetic ketoacidosis (DKA) was defined as pH <7.30 combined with hyperglycemia and ketonemia or ketonuria (11). HbA1c analysis was performed at the hospitals according to their laboratory method and quality assured by the External Quality Assurance in Laboratory Medicine in Sweden (12). GADA, IA-2A, insulin autoantibodies (IAA), ZnT8RA, ZnT8WA, and ZnT8QA autoantibodies were analyzed. Methods of analyses of antibodies and HLA-DQA1 and HLA-DQB1 genotypes in BDD have been described previously (9). HLA types were classified into four risk groups: HLA-DQ2/8, HLA-DQ8/X (where X is not 2), HLA-DQ2/X (where X is not 8), and HLA-DQX/X (where X is neither 2 nor 8) (13).
For analysis of first-generation family history of diabetes between the BDD cohort and the reference groups, only BDD data from children aged 11–13 years (born 1992–1999) with parental diabetes were compared with those of children without diabetes from cohorts of 12-year-olds in 2005 (born in 1993) and 2009 (born in 1997) from the Exploring the Iceberg of Celiacs in Sweden (ETICS) study. ETICS was a population-based, cross-sectional screening study for celiac disease including 13,279 participating children, and parental family history of type 1 and T2D was collected through a questionnaire answered by 11,050 children and their families (14). For the analysis of clinical characteristics within the BDD study, both first- and second-generation family histories were used.
Relative risk (RR) with 95% CI was used in univariable analyses for comparisons between the BDD cohort and the reference cohort and to compare BMI and DKA between the family history groups within the BDD cohort. Logistic regression models, using sex and age-groups as covariates, were applied to DKA and BMI analyses to verify that univariable analyses were appropriate. Results from logistic regression analyses supported the use of RRs. ANOVA, χ2, and Kruskall-Wallis tests were used for comparisons between groups. The Benjamini-Hochberg procedure was used to control the false-positive rate. We used IBM SPSS, version 27, and Microsoft Excel software. The significance level was set to 0.05.
Ethical Considerations
The study was approved by the Ethical Review Board at Karolinska Institute, Stockholm, Sweden (Dnr 2004/826-1 with amendments 2006/108-32/1, 2007/1383-32/1). Oral and written information was provided, and informed consent was given.
Results
Prevalence of Family History of Diabetes
In the BDD cohort, of the 3,603 children, 40.5% had a first- or second-generation family history of diabetes: 12.3% T1D, 32.7% T2D, and 4.4% had family histories of both type 1 and T2D. Children with T1D were more likely to have a father or grandfather with T1D or T2D than a mother or grandmother with either of them (Fig. 2).
Among the 11- to 13-year-old children in the BDD cohort (n = 801), 8.4% had a parent with T1D and 3.5% had a parent with T2D, compared with the reference group (n = 11,050), in which 2.1% had a parent with T1D, and 1.9% had a parent with T2D (10). There was a 3.93 (95% CI 3.03–5.11) increased risk of having a parent with T1D (P < 0.0001) and a 1.88 (95% CI 1.27–2.76) increased risk of having a parent with T2D (P = 0.002), comparing the BDD cohort with the reference cohort (Fig. 1), with similar results between sexes.
Comparison of first-generation family history of type 1 and T2D between 11- to 13-year-old children with T1D in BDD cohort and 12-year-old children without diabetes in the reference group.
Comparison of first-generation family history of type 1 and T2D between 11- to 13-year-old children with T1D in BDD cohort and 12-year-old children without diabetes in the reference group.
Family history of diabetes in children with T1D, grouped by first- and second-generation relatives, and stratified on sex of the parents and grandparents. Data are presented as n (%). Comparison of both maternal and paternal grandmothers compared with grandfathers also was significantly less common with family history of both T1D (P < 0.01) and T2D (P = 0.001).
Family history of diabetes in children with T1D, grouped by first- and second-generation relatives, and stratified on sex of the parents and grandparents. Data are presented as n (%). Comparison of both maternal and paternal grandmothers compared with grandfathers also was significantly less common with family history of both T1D (P < 0.01) and T2D (P = 0.001).
Family History and Clinical Characteristics
In total, 10.4% of patients in the BDD cohort were overweight or obese. The corresponding proportions for children with a family history of T1D were 12.7% and 11.9% for those with T2D (Tables 1 and 2). Children with a family history of T2D were more likely to be overweight or obese compared with children without a family history of diabetes (P = 0.002), with a larger risk for boys (Table 2).
Baseline characteristics at diagnosis based on family history of diabetes
. | Total BDD cohort (N = 3,603) . | Family history of diabetes . | |||
---|---|---|---|---|---|
. | None (n = 1,949) . | T1D (n = 283) . | T2D (n = 1,017) . | T1D + T2D (n = 160) . | |
Boys, n (%) | 2,007 (56) | 1,075 (55) | 158 (58) | 574 (57) | 100 (63) |
Age, mean (95% CI), years | 9.9 (9.8–10.1) | 9.6 (9.4–9.8) | 9.4 (8.8–9.9) | 10.5 (10.3–10.8) | 10.1 (9.4–10.8) |
BMI, mean (95% CI), kg/m2 | 17.2 (17.1–17.3) | 16.9 (16.7–17.0) | 17.5 (17.1–17.9) | 17.7 (17.4–17.9) | 17.9 (17.3–18.5) |
HbA1c, mean (95% CI), mmol/mol | 93.8 (93.0–94.7) | 94.7 (93.5–95.8) | 82.1 (79.3–85.0) | 96.6 (95.0–98.2) | 86.0 (82.2–89.9) |
High-risk HLA (DQ2/8), n (%) | 1014 (30) | 610 (31) | 83 (29) | 278 (27) | 43 (27) |
GADA positive, n (%) | 1,934 (57) | 1,084 (56) | 161 (57) | 593 (58) | 96 (60) |
IAA positive, n (%) | 1,126 (33) | 662 (34) | 98 (35) | 315 (31) | 51 (32) |
Overweight or obesity, n (%) | 332 (11) | 162 (8.9) | 31 (12) | 119 (13) | 20 (13) |
DKA at diagnosis, n (%) | 504 (14) | 284 (16) | 42 (17) | 164 (16) | 14 (18) |
Antibody negative, n (%) | 247 (6.8) | 148 (6.8) | 21 (7.4) | 66 (6.5) | 12 (7.5) |
. | Total BDD cohort (N = 3,603) . | Family history of diabetes . | |||
---|---|---|---|---|---|
. | None (n = 1,949) . | T1D (n = 283) . | T2D (n = 1,017) . | T1D + T2D (n = 160) . | |
Boys, n (%) | 2,007 (56) | 1,075 (55) | 158 (58) | 574 (57) | 100 (63) |
Age, mean (95% CI), years | 9.9 (9.8–10.1) | 9.6 (9.4–9.8) | 9.4 (8.8–9.9) | 10.5 (10.3–10.8) | 10.1 (9.4–10.8) |
BMI, mean (95% CI), kg/m2 | 17.2 (17.1–17.3) | 16.9 (16.7–17.0) | 17.5 (17.1–17.9) | 17.7 (17.4–17.9) | 17.9 (17.3–18.5) |
HbA1c, mean (95% CI), mmol/mol | 93.8 (93.0–94.7) | 94.7 (93.5–95.8) | 82.1 (79.3–85.0) | 96.6 (95.0–98.2) | 86.0 (82.2–89.9) |
High-risk HLA (DQ2/8), n (%) | 1014 (30) | 610 (31) | 83 (29) | 278 (27) | 43 (27) |
GADA positive, n (%) | 1,934 (57) | 1,084 (56) | 161 (57) | 593 (58) | 96 (60) |
IAA positive, n (%) | 1,126 (33) | 662 (34) | 98 (35) | 315 (31) | 51 (32) |
Overweight or obesity, n (%) | 332 (11) | 162 (8.9) | 31 (12) | 119 (13) | 20 (13) |
DKA at diagnosis, n (%) | 504 (14) | 284 (16) | 42 (17) | 164 (16) | 14 (18) |
Antibody negative, n (%) | 247 (6.8) | 148 (6.8) | 21 (7.4) | 66 (6.5) | 12 (7.5) |
Presentation of different characteristics at diagnosis of T1D among children from the BDD cohort. Grouped by differences in family history (first and second generation) of T1D, T2D, both T1D and T2D, or no family history of diabetes. GADA, GAD antibody; IAA, insulin autoantibody.
Differences in clinical characteristics at T1D diagnosis
. | No family history . | T1D . | T2D . | T1D + T2D . | Total . | Missing data . | P value (trend) . | Adjusted P value . |
---|---|---|---|---|---|---|---|---|
Total, n | 1,949 | 283 | 1,017 | 160 | 3,603 | |||
Girls, n | 874 | 125 | 443 | 60 | 1,596 | |||
Boys, n | 1,075 | 158 | 574 | 100 | 2,007 | |||
BMI, n (%) | ||||||||
BDD | ||||||||
Overweight or obesity, n (%) | 162 (9.2) | 31 (12) | 119 (13) | 20 (13) | 2,007 | 416 (12) | ||
RR vs. normal weight (95% CI); P value | 1.35 (0.94–1.94); P = 0.102 | 1.41 (1.13–1.76); P = 0.002 | 1.46 (0.94–2.25); P = 0.089 | |||||
Girls | ||||||||
Overweight or obesity, n (%) | 59 (7.5) | 11 (10) | 36 (9.2) | 8 (15) | 114 (8.5) | 194 (12) | ||
RR vs. normal weight (95% CI); P value | 1.39 (0.75–2.55); P = 0.295 | 1.22 (0.82–1.82); P = 0.319 | 1.98 (0.99–3.93); P = 0.003 | |||||
Boys | ||||||||
Overweight or obesity, n (%) | 103 (11) | 20 (14) | 83 (16) | 12 (13) | 218 (13) | 222 (11) | ||
RR vs. normal weight (95% CI); P value | 1.32 (0.85–2.06); P = 0.226 | 1.50 (1.15–1.97); P = 0.003 | 1.19 (0.68–2.08); P = 0.543 | |||||
HLA, n (%) | ||||||||
DQ2/DQ8 | 610 (32) | 83 (30) | 278 (28) | 43 (27) | 1014 (30) | 46 (1.3) | T1D vs. none = 0.71 T2D vs. none = 0.32 T1D vs. T2D = 0.71 | |
Age, mean (95% CI), years | ||||||||
BDD | 9.6 (9.4–9.8) | 9.4 (8.8–9.9) | 10.5 (10.3–10.8) | 10.1 (9.4–10.8) | 9.9 (9.8–10.1) | <0.001 | T1D vs. none = 0.880 T2D vs. none <0.001 T1D vs. T2D <0.001 | |
Girls | 9.5 (9.3–9.7) | 9.4 (9.1–9.7) | 8.6 (7.9–9.4) | 10.1 (9.7–10.5) | 9.3 (8.1–10.6) | <0.001 | ||
Boys | 9.9 (9.7–10.2) | 9.9 (9.2–10.6) | 10.9 (10.5–11.2) | 10.6 (9.8–11.4) | 10.2 (10.0–10.4) | <0.001 | ||
HbA1c, mean (95% CI) | ||||||||
BDD | 94.7 (93.5–95.8) | 82.1 (79.3–85.0) | 96.6 (95.0–98.2) | 86.0 (82.2–89.9) | 93.8 (93.0–94.7) | 285 (7.9) | <0.001 | T1D vs. none <0.0001 T2D vs. none = 0.408 T1D vs. T2D <0.0001 |
Girls | 97.3 (95.6–99.0) | 81.2 (77.0–85.5) | 100 (97.4–103) | 81.8 (75.4–88.2) | 96.2 (94.8–97.5) | 128 (8.0) | <0.001 | |
Boys | 92.0 (90.9–93.1) | 92.5 (91.1–94.0) | 82.9 (78.9–86.8) | 94.0 (92.0–96.0) | 88.6 (83.8–93.3) | 157 (7.8) | <0.001 | |
0–5.9 years | 81.7 (80.0–83.3) | 70.8 (67.6–74.0) | 80.0 (77.0–82.9) | 71.8 (66.3–77-4) | 79.8 (78.4–81.1) | 81 (10) | <0.001 | |
6–11.9 years | 95.5 (93.8–97.3) | 81.0 (76.7–85.2) | 96.0 (93.6–98.3) | 86.4 (80.4–92.5) | 93.9 (92.6–95.2) | 100 (7.0) | <0.001 | |
12–17.9 years | 103 (101–103) | 93.6 (87.6–99.6) | 104 (102–107) | 94.7 (88.2–101) | 102 (101–104) | 104 (7.8) | <0.001 |
. | No family history . | T1D . | T2D . | T1D + T2D . | Total . | Missing data . | P value (trend) . | Adjusted P value . |
---|---|---|---|---|---|---|---|---|
Total, n | 1,949 | 283 | 1,017 | 160 | 3,603 | |||
Girls, n | 874 | 125 | 443 | 60 | 1,596 | |||
Boys, n | 1,075 | 158 | 574 | 100 | 2,007 | |||
BMI, n (%) | ||||||||
BDD | ||||||||
Overweight or obesity, n (%) | 162 (9.2) | 31 (12) | 119 (13) | 20 (13) | 2,007 | 416 (12) | ||
RR vs. normal weight (95% CI); P value | 1.35 (0.94–1.94); P = 0.102 | 1.41 (1.13–1.76); P = 0.002 | 1.46 (0.94–2.25); P = 0.089 | |||||
Girls | ||||||||
Overweight or obesity, n (%) | 59 (7.5) | 11 (10) | 36 (9.2) | 8 (15) | 114 (8.5) | 194 (12) | ||
RR vs. normal weight (95% CI); P value | 1.39 (0.75–2.55); P = 0.295 | 1.22 (0.82–1.82); P = 0.319 | 1.98 (0.99–3.93); P = 0.003 | |||||
Boys | ||||||||
Overweight or obesity, n (%) | 103 (11) | 20 (14) | 83 (16) | 12 (13) | 218 (13) | 222 (11) | ||
RR vs. normal weight (95% CI); P value | 1.32 (0.85–2.06); P = 0.226 | 1.50 (1.15–1.97); P = 0.003 | 1.19 (0.68–2.08); P = 0.543 | |||||
HLA, n (%) | ||||||||
DQ2/DQ8 | 610 (32) | 83 (30) | 278 (28) | 43 (27) | 1014 (30) | 46 (1.3) | T1D vs. none = 0.71 T2D vs. none = 0.32 T1D vs. T2D = 0.71 | |
Age, mean (95% CI), years | ||||||||
BDD | 9.6 (9.4–9.8) | 9.4 (8.8–9.9) | 10.5 (10.3–10.8) | 10.1 (9.4–10.8) | 9.9 (9.8–10.1) | <0.001 | T1D vs. none = 0.880 T2D vs. none <0.001 T1D vs. T2D <0.001 | |
Girls | 9.5 (9.3–9.7) | 9.4 (9.1–9.7) | 8.6 (7.9–9.4) | 10.1 (9.7–10.5) | 9.3 (8.1–10.6) | <0.001 | ||
Boys | 9.9 (9.7–10.2) | 9.9 (9.2–10.6) | 10.9 (10.5–11.2) | 10.6 (9.8–11.4) | 10.2 (10.0–10.4) | <0.001 | ||
HbA1c, mean (95% CI) | ||||||||
BDD | 94.7 (93.5–95.8) | 82.1 (79.3–85.0) | 96.6 (95.0–98.2) | 86.0 (82.2–89.9) | 93.8 (93.0–94.7) | 285 (7.9) | <0.001 | T1D vs. none <0.0001 T2D vs. none = 0.408 T1D vs. T2D <0.0001 |
Girls | 97.3 (95.6–99.0) | 81.2 (77.0–85.5) | 100 (97.4–103) | 81.8 (75.4–88.2) | 96.2 (94.8–97.5) | 128 (8.0) | <0.001 | |
Boys | 92.0 (90.9–93.1) | 92.5 (91.1–94.0) | 82.9 (78.9–86.8) | 94.0 (92.0–96.0) | 88.6 (83.8–93.3) | 157 (7.8) | <0.001 | |
0–5.9 years | 81.7 (80.0–83.3) | 70.8 (67.6–74.0) | 80.0 (77.0–82.9) | 71.8 (66.3–77-4) | 79.8 (78.4–81.1) | 81 (10) | <0.001 | |
6–11.9 years | 95.5 (93.8–97.3) | 81.0 (76.7–85.2) | 96.0 (93.6–98.3) | 86.4 (80.4–92.5) | 93.9 (92.6–95.2) | 100 (7.0) | <0.001 | |
12–17.9 years | 103 (101–103) | 93.6 (87.6–99.6) | 104 (102–107) | 94.7 (88.2–101) | 102 (101–104) | 104 (7.8) | <0.001 |
Results of analyses of clinical characteristics at diagnosis of T1D between groups of family history of T1D, T2D, both T1D and T2D, or no family history of diabetes. RR of overweight or obesity, stratified by sex. HLA-genotype, comparison of proportion of DQ2/DQ8. Mean age and mean HbA1c (stratified by sex and age), with 95% CI, and results of ANOVA calculations, presented with P value for trend and specifically for HbA1c and age comparison between heredity groups in the entire BDD cohort.
Independent of age, children with a family history of T1D had lower mean HbA1c levels at diagnosis. Children with a family history of T1D were younger at diagnosis than those with a family history of T2D and those without a family history of diabetes (Tables 1 and 2).
Children with a family history of T2D were less likely to carry the DQ2/8 haplotype than those without a family history of diabetes (P = 0.02), though the result was not statistically significant after adjusting for multiple comparisons (adjusted P = 0.32) (Table 2 and Supplementary Table 1). There were no differences in autoantibodies and DKA between family history groups (Supplementary Tables 2 and 3). Overall, the differences between clinical characteristics at diagnosis were rather small between the groups (Table 1).
Conclusions
In this nationwide Swedish cohort, a family history not only of T1D but also T2D was more common in children with T1D compared with children without diabetes. Among children with T1D, individuals with a family history of T2D were more likely to have overweight or obesity.
These results suggest that a family history of T2D increases the risk of T1D and being overweight, or that there are shared genetic or environmental risk factors between these conditions. Previous data support that being overweight or obese increases the risk of T1D (15–20). We previously reported a changing pattern of clinical phenotypes and HLA genotypes over time and an association between increased BMI and low-risk HLA at onset of T1D (6). Interestingly, children with T1D and a family history of T2D in the present study tended to less often carry the high-risk HLA genotype than children without a family history of T2D. However, a Finnish study observed no differences between HLA type in children with a family history of T2D and those without (16).
This study compared a large nationwide cohort with a general population reference group of similar ages and birth periods. The risk of misclassification of diabetes among family members was minimized by professional help in completing the study questionnaire. Although the reference group provided a comparison of the family history of children without T1D, it was not a matched control group, and the data were based on self-reported questionnaires. Also, we were unable to control for overweight among parents.
In summary, a family history of T2D was more common in children with T1D than in healthy peers and was also associated with a different clinical picture at diagnosis of T1D. These findings underscore the importance of considering familial diabetes history for understanding the clinical heterogeneity of pediatric T1D, and also support the concept that having T2D and overweight or obesity may contribute to the development of T1D.
This article contains supplementary material online at https://doi.org/10.2337/figshare.26866693.
Article Information
Acknowledgments. The authors thank Qefsere Brahimi for help with preparing the data and other assistance.
Funding. This study was financially supported by grants from the Swedish Child Diabetes Foundation (Barndiabetesfonden), the Samariten Foundation for Paediatric Research, and from Region Skånes Research and Development Fund. It was also supported by the Swedish Research Council, Dnr 2009-1039 and Dnr 349-2006-237, and by the Swedish Foundation for Strategic Research, Dnr IRC15-0067.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Author Contributions. A.C., J.L., H.E.L., G.F., C.M., and M.P. (the BDD steering group) acquired the data. E.H., L.L., and A.C. took part in conception and design of the study, researched data, performed the statistical analysis of the data, contributed to discussion, wrote the draft of the first manuscript, and reviewed and edited the manuscript. H.E.L., J.L., C.M., M.P., and G.F. took part in conception and design of the study, contributed to discussion, and reviewed and edited the manuscript substantially. F.N. helped with the statistical analysis of the data, contributed to discussion, and reviewed and edited the manuscript. L.L. and J.T. contributed to discussion and reviewed and edited the manuscript. All authors approved the final version of the manuscript. A.C. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. This research was previously presented as a poster at the International Society for Paediatric and Adolescent Diabetes meeting, Abu Dhabi, 15 October 2022, including a printed abstract; and at the Scandinavian Society for the Study of Diabetes meeting, Aarhus, Denmark, 26 May 2023.
Handling Editors. The journal editors responsible for overseeing the review of the manuscript were John B. Buse and Kristen J. Nadeau.